The likelihood of a chromosomally abnormal conception increases strikingly with age, and is a contributory factor in the age- related decrease in fertility in women. The consequences of these errors to human health are profound. The most common type of abnormality, aneuploidy, is the leading cause of mental retardation and pregnancy failure in our species. The basis of the age effect remains unknown, but recent molecular studies indicate that meiosis I (MI, the time at which homologous chromosomes segregate) is a critical time point in the genesis of most meiotic errors. In this proposal we outline direct studies of human oocytes to examine the mechanism of non-disjunction and the age association for individual human chromosomes. In addition, we propose experimental studies using mouse oocytes to examine the factors that influence the mammalian female meiotic process. These experimental studies make use of mouse mutants and recently developed culture systems for the in vitro growth of murine oocytes as model systems for the study of age-related changes in the human meiotic process. Finally, the possibility that the early cleavage divisions of the mammalian embryo are prone to non-disjunction errors is addressed using a murine mutation with a high level of mitotic non-disjunction. The combined data from the proposed studies will provide information on the mechanism(s) responsible for the human maternal age effect. Ultimately this knowledge may be useful in refining the current procedures for human assisted reproduction and/or in designing programs for clinical intervention to provide women over the age of 35 with increased likelihood of achieving a normal pregnancy.